Intracellular trafficking and processing of amyloid precursor protein (APP) likely plays a major role in the pathology of AD. However, the characteristic features of beta-peptide deposition have not yet been mimicked in a tissue culture model. Most importantly, the propagation of misfolded protein responses from cell to cell has received relatively little attention. We have initiated a collboration with an expert in the field of intra-cellular chaperones to address this question. We propose to: 1) Study the role of normal and a series of mutant chaperones in the transport and processing of APP to the cell surface. The mutant chaperone genes will be provided by our collaborator. 2) Study the association of mutant forms of APP with a variety of trafficking chaperones using fluorescently tagged proteins and fluorescence energy transfer monitored by 3D confocal microscopy. We will generate tagged APP and tau, while tagged chaperones will be provided by our collaborator. Tagged genes will be co-expressed by transfection into neuronal and non-neuronal cell lines in culture. 3) Study the propagation of mutant beta peptide to neighbouring cells. These studies are just being initiated